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Attenuation of Cocaine Self‐Administration by Dual Inhibition of the Dopamine Transporter and Sigma Receptors
Author(s) -
Hiranita Takato,
Newman Amy H.,
Katz Jonathan L.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.588.5
Subject(s) - dopamine transporter , pharmacology , self administration , chemistry , dopamine , sigma receptor , agonist , receptor , endocrinology , medicine , biochemistry , dopaminergic
Previous studies have indicated that sigma receptor (σR) antagonists decrease reinforcing effects of cocaine in place conditioning, but not self‐administration (SA) procedures. The present study further examined σR involvement in cocaine SA. Rats trained to self administer cocaine exhibited maximal increases in responding compared to vehicle at 0.32 mg/kg/injection and lower rates at other doses. The σR agonists, DTG and PRE‐084, but not standard σR antagonists (BD 1008, BD 1047, BD 1063, AC 927, NE 100), maintained SA like cocaine, with PRE‐084 being 10‐fold more potent than DTG. The σR antagonists had no effect on cocaine SA across a range of doses. DTG and PRE‐084 as well as ligands for the dopamine transporter (DAT) shifted the cocaine dose‐effect curve leftward. In addition, σR agonist SA was dose‐dependently blocked by standard σR antagonists, and analogues of rimcazole which also bind to the DAT. In contrast to standard σR antagonists, rimcazole analogues also decreased cocaine SA. Further, combinations of standard σR antagonists with the DAT inhibitor, WIN 35,428, decreased cocaine SA. Rimcazole analogues were more potent in decreasing responding maintained by cocaine than food. These findings suggest that 1) σR agonists can have reinforcing effects in rats trained to self‐administer cocaine, and 2) cocaine SA can be attenuated by dual inhibition of the DAT and σRs.